Search

Abstract Objective Rare and complex epilepsies encompass a diverse range of disorders characterized by seizures. We aimed to establish a consensus on key issues related to these conditions through collaboration among experienced neurologists, neuropediatricians, and patient advocacy representatives. Methods Employing a modified Delphi method, a scientific board comprising 20 physicians and 4 patient advocacy representatives synthesized existing literature with their expertise to formulate statements on contentious topics. A final 32‐member expert panel, representing diverse regions of Italy, validated these statements through a two‐round voting process, with consensus defined as an average score ≥7. Results Sixteen statements reached a consensus, emphasizing the necessity for epidemiological studies to ascertain the true prevalence of rare epilepsies. Etiology emerged as a crucial factor influencing therapeutic strategies and outcome prediction, with particular concern regarding prolonged and tonic–clonic seizures. The importance of early implementation of specific drugs and non‐pharmacological interventions in the treatment algorithm for developmental and epileptic encephalopathies (DEEs) was underscored. Multidisciplinary care involving experts with diverse skills was deemed essential, emphasizing non‐seizure outcomes in adolescence and adulthood. Significance This national consensus underscores the imperative for personalized, comprehensive, and multidisciplinary management of rare epilepsies/DEEs. It advocates for increased research, particularly in epidemiology and therapeutic approaches, to inform clinical decision‐making and healthcare policies, ultimately enhancing patients' outcomes. Plain Language Summary The modified Delphi method is broadly used to evaluate debated topics. In this work, we sought the consensus on integrated and social care in epilepsy management. Both representatives of high‐level epilepsy centers and patients' caregivers were directly involved.

Abstract Objective The increasingly rapid pace of advancement in genetic testing may lead to inequalities in technical and human resources with a negative impact on optimal epilepsy clinical practice. In this view, the European Reference Network (ERN) for Rare and Complex Epilepsies EpiCARE conducted a survey addressing several aspects of accessibility, availability, costs, and standard practices on genetic testing across ERN EpiCARE centers. Methods An online Google form was sent to 70 representatives of ERN EpiCARE centers. Descriptive statistics and qualitative analysis were used for data presentation. Results We received 45 responses (1/center) representing 23 European countries with a better representation of Western Europe. Forty‐five percent of the centers did not have access to all available types of genetic testing, mainly reflecting the limited availability of whole‐genome sequencing (WGS). Thirty‐five percent of centers report cost coverage only for some of the available tests, while costs per test varied significantly (interquartile range IQR ranging from 150 to 1173 euros per test across centers). Urgent genetic testing is available in 71.7% of countries (time‐to‐urgent result: 2 day to 2 months). The average time‐to‐result of specific tests in case of non‐urgent prescription has a significant variance across centers, with the biggest range observed for whole‐exome sequencing (6–128 weeks, IQR: 27 weeks). The percentage of agreement among the experts regarding the choice of genetic test at first intention in specific clinical situations was in all cases less than 50 percent (34.9% to 47% according to the proposed scenarios). Significance Costs, time to deliver the results to the clinician, and type of first‐line genetic testing vary widely across Europe, even in countries where ERN EpiCARE centers are present. Increased availability of genetic tests and guidance for optimal test choices in epilepsy remains essential to avoid diagnostic delays and excess health costs. Plain Language Summary The survey of the ERN EpiCARE highlights disparities in genetic testing for epilepsy across 45 ERN EpiCARE centers in 23 European countries. The findings reveal variable access to certain genetic tests, with lowest access to WGS. Costs and time‐to‐results vary widely. Urgent genetic testing is available in 71.7% of countries. Agreement among experts on first‐line genetic tests for specific patient scenarios is below 50%. The study emphasizes the need for improved test availability and guidance to avoid diagnostic delays and unnecessary costs. EpiCARE has the mission to contribute in homogenizing best practices across Europe.

Introduction Lafora disease (LD) is an ultrarare fatal progressive myoclonic epilepsy, causing drug-resistant epilepsy, myoclonus and psychomotor deterioration. LD is caused by mutations in EPM2A or NHLRC1, which lead to the accumulation of polyglucosans in the brain and neurodegeneration. There are no approved treatments for LD. VAL-1221 is a fusion protein comprising the Fab portion of a cell-penetrating antibody and recombinant human acid alpha glucosidase, and has demonstrated an ability to clear polyglucosans. We hypothesise that intravenous infusion of VAL-1221 might be able to degrade cerebral polyglucosans and stabilise or improve disease outcomes. The aim of this study is to assess the safety and preliminary efficacy of VAL-1221 in patients with LD.Methods and analysis The study is a phase 2, single-arm, open-label, baseline-controlled clinical trial which will be conducted in a single investigational study centre in Italy, namely the sponsor ‘IRCCS Istituto delle Scienze Neurologiche di Bologna—Azienda USL di Bologna’. The study will enrol six genetically confirmed patients with mid- to late-stage LD. The global duration of the study for each participant will be 18 months, including screening period, open-label treatment (12 months) and follow-up period. VAL-1221 20 mg/kg will be administered as an intravenous infusion every week for 3 weeks, then every other week. Patients will undergo full clinical assessments at baseline, at an intermediate and at the end-of-treatment visit. The primary objective is to evaluate the safety. The exploratory efficacy endpoints will be related to epilepsy, neuropsychological and motor functions, global assessment and disease burden, in addition to biomarkers. Statistical analyses will be primarily descriptive.Ethics and dissemination The study protocol was approved by the local ethics committee (number 232-2023-FARM-AUSLBO-23020, 22 March 2023). The results of this study will be disseminated by the investigators through presentations at international scientific conferences and reported in peer-reviewed scientific journals.Trial registration number European Union Clinical Trials Register (EudraCT 2023-000185-34).

Hyperventilation (HV) is an activation technique performed during clinical practices to trigger epileptiform activities, supporting the neurophysiological evaluation of patients with epilepsy. Although the role of HV has often been questioned, especially in the case of focal epilepsy, no studies have ever assessed how cortical structures respond to such a maneuver via intracranial EEG recordings. This work aims to fill this gap by evaluating the HV effects on the Stereo-EEG (SEEG) signals from a cohort of 10 patients with drug-resistant focal epilepsy. We extracted multiple quantitative metrics from the SEEG signals and compared the results obtained during HV, awake status, non-REM sleep, and seizure onset. Our findings show that the cortical connectivity, estimated via the phase transfer entropy (PTE) algorithm, strongly increases during the HV maneuver, similar to non-REM sleep. The opposite effect is observed during seizure onset, as ictal transitions involve the desynchronization of the brain structures within the epileptogenic zone. We conclude that HV promotes a conductive environment that may facilitate the propagation of epileptiform activities but is not sufficient to trigger seizures in focal epilepsy.

Epileptologists and psychiatrists have long observed a correlation between epilepsy and personality disorders (PDs) in their clinical practice. We conducted a comprehensive PubMed search looking for evidence on PDs in people with epilepsy (PwE). Out of over 600 results obtained without applying any time restriction, we selected only relevant studies (both analytical and descriptive) limited to English, Italian, French and Spanish languages, with a specific focus on PDs, rather than traits or symptoms, thus narrowing our search down to 23 eligible studies. PDs have been investigated in focal epilepsy (predominantly temporal lobe epilepsy - TLE), juvenile myoclonic epilepsy (JME) and psychogenic non-epileptic seizures (PNES), with heterogeneous methodology. Prevalence rates of PDs in focal epilepsy ranged from 18 to 42% in surgical candidates or post-surgical individuals, with Cluster C personality disorders or related traits and symptoms being most common. In JME, prevalence rates ranged from 8 to 23%, with no strong correlation with any specific PDs subtype. In PNES, prevalence rates ranged from 30 to 60%, with a notable association with Cluster B personality disorders, particularly borderline personality disorder. The presence of a PD in PwE, irrespective of subtype, complicates treatment management. However, substantial gaps of knowledge exist concerning the neurobiological substrate, effects of antiseizure medications and epilepsy surgery on concomitant PDs, all of which are indeed potential paths for future research.

Abstract Background Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype–phenotype correlations. Methods We collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy. Results 250 cases described in 70 articles were included. The mutated gene was NHLRC1 in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95% CI 1.23–6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95% CI 0.75–5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1 genotype was confirmed to have a more favourable prognosis in terms of disease duration. Conclusions This study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis.

Abstract We describe a case of epileptic encephalopathy in a young woman with undiagnosed medium‐chain acyl‐coenzyme A dehydrogenase deficiency (MCADD), who presented with an early‐onset focal motor status epilepticus (SE) then followed by permanent left hemiplegia and drug‐resistant epilepsy with neurodevelopmental delay. Throughout her clinical history, recurrent episodes of lethargy, feeding difficulties, and clustering seizures occurred, progressing into a super refractory SE and death at the age of 25 years. Although epilepsy is not a distinctive feature of MCADD, we advise considering this metabolic disease as a possible etiology of epileptic encephalopathy and hemiconvulsion‐hemiplegia‐epilepsy syndrome of unknown origin, on the chance to provide a timely and targeted treatment preventing development delay and evolution to SE. Adult patients with epilepsy of unknown etiology not screened at birth for inborn errors of metabolism, such as MCADD, should be promptly investigated for these treatable conditions.

Abstract Objective Perampanel (PER) is indicated as adjunctive antiseizure medication (ASM) in adolescents and adults with epilepsy. Data from clinical trials show good efficacy and tolerability, while limited information is available on the routine clinical use of PER, especially when used as only add‐on treatment. Methods We performed an observational, retrospective, multicenter study on people with focal or generalized epilepsy aged >12 years, consecutively recruited from 52 Italian epilepsy centers. All patients received PER as the only add‐on treatment to a background ASM according to standard clinical practice. Retention rate, seizure frequency, and adverse events were recorded at 3, 6, and 12 months after PER introduction. Subanalyses by early or late use of PER and by concomitant ASM were also conducted. Results Five hundred and three patients were included (age 36.5 ± 19.9 years). Eighty‐one percent had focal epilepsy. Overall, the retention rate was very high in the whole group (89% at 12 months) according with efficacy measures. No major differences were observed in the subanalyses, although patients who used PER as early add‐on, as compared with late add‐on, more often reached early seizure freedom at 3‐month follow‐up (66% vs 53%, P = .05). Treatment‐emergent adverse events occurred in 25%, far less commonly than in PER randomized trials. Significance This study confirms the good efficacy and safety of PER for focal or generalized epilepsy in real‐life conditions. We provide robust data about its effectiveness as only add‐on treatment even in patients with a long‐standing history of epilepsy and previously treated with many ASMs.

A stepwise increase in the utilization of ketogenic dietary therapies for drug-resistant epilepsy has been observed in Italy in the last decade, although it is still considered often underused in many centers when compared to other countries. The Dietary Therapy Study Group of the Italian League against Epilepsy proposes practical recommendations to improve shared knowledge and facilitate the application of ketogenic dietary therapies, optimizing its efficacy and tolerability. The experts involved (11 child neuropsychiatrists, two adult neurologists, one psychologist, one pharmacologist, one pediatric endocrinologist, one representative of patients' associations, and three dietitians and clinical nutritionists) responded to a survey on current clinical practice issues and were asked to discuss controversial topics related to supplementation, long-term maintenance, transition, and a multidisciplinary approach to ketogenic dietary therapies. Practical indications for patient selection, diet initiation, management, side effects prevention, and follow-up are provided.

PurposeTo evaluate the electro-clinical features in association with laboratory and instrumental correlates of neurodegeneration to detect the progression of Lafora disease (LD).MethodsWe investigated the electro-clinical longitudinal data and CSF Aβ42, p-tau181 and t-tauAg, amyloid, and 18F-FDG PET of five unrelated LD families.ResultsThree progressive electro-clinical stages were identified. The early phase was characterized by rare, generalized tonic-clonic and focal visual seizures, followed by the occurrence of myoclonus after a period ranging from 2 to 12 months. The intermediate stage, usually occurring 2 years after the onset of epilepsy, is characterized by a worsening of epilepsy and myoclonus associated with progressive dementia and cerebellar signs. Finally, the late stage, evolving after a mean period of 7 ± 1.41 years from the onset of the disease, was characterized by gait ataxia resulting in bedriddenness, severe dementia, daily/pluri-daily myoclonus, drug-resistant epilepsy, clusters of seizures or status epilepticus, and medical complications. Amyloid (CSF Aβ42, amyloid PET) and neurodegenerative (CSF p-tau181 and t-tauAg, FDG-PET) biomarkers indicate a pattern of cognitive impairment of the non-Alzheimer's disease type. A total of 80% of the LD patients showed more severe hypometabolism in the second FDG-PET scan compared to the first scan performed in a lower phase; the lateral temporal lobe and the thalamus hypometabolism were associated with the presence of intermediate or late phase.ConclusionsThree electroclinical and 18F-FDG PET evolutive stages are useful biomarkers for the progression of LD and could help to evaluate the efficacy of new disease-modifying treatments. The combination of traditional CSF biomarkers improves the diagnostic accuracy of cognitive decline in LD patients, indicating a cognitive impairment of the non-Alzheimer's disease type.

Objectives: To explore the neuropsychological profile and the integrity of the olfactory network in patients with COVID-19-related persistent olfactory dysfunction (OD). Methods: Patients with persistent COVID-19-related OD underwent olfactory assessment with Sniffin’ Sticks and neuropsychological evaluation. Additionally, both patients and a control group underwent brain MRI, including T1-weighted and resting-state functional MRI (rs-fMRI) sequences on a 3 T scanner. Morphometrical properties were evaluated in olfaction-associated regions; the rs-fMRI data were analysed using graph theory at the whole-brain level and within a standard parcellation of the olfactory functional network. All the MR-derived quantities were compared between the two groups and their correlation with clinical scores in patients were explored. Results: We included 23 patients (mean age 37 ± 14 years, 12 females) with persistent (mean duration 11 ± 5 months, range 2–19 months) COVID-19-related OD (mean score 23.63 ± 5.32/48, hyposmia cut-off: 30.75) and 26 sex- and age-matched healthy controls. Applying population-derived cut-off values, the two cognitive domains mainly impaired were visuospatial memory and executive functions (17 % and 13 % of patients). Brain MRI did not show gross morphological abnormalities. The lateral orbital cortex, hippocampus, and amygdala volumes exhibited a reduction trend in patients, not significant after the correction for multiple comparisons. The olfactory bulb volumes did not differ between patients and controls. Graph analysis of the functional olfactory network showed altered global and local properties in the patients’ group (n = 19, 4 excluded due to artifacts) compared to controls. Specifically, we detected a reduction in the global modularity coefficient, positively correlated with hyposmia severity, and an increase of the degree and strength of the right thalamus functional connections, negatively correlated with short-term verbal memory scores. Discussion: Patients with persistent COVID-19-related OD showed an altered olfactory network connectivity correlated with hyposmia severity and neuropsychological performance. No significant morphological alterations were found in patients compared with controls.

Radiofrequency thermocoagulation (RF-TC) is a wide-used procedure for drug-resistant epilepsy. The technique is considered safe with an overall risk of 1.1% of permanent complications, mainly focal neurological deficits. We report the case of a patient with drug-resistant epilepsy who complained of immediate seizure worsening and an unexpected event seven months following RF-TC.A 35-year-old male with drug-resistant epilepsy from the age of 18 years underwent stereoelectroencephalography (SEEG) implantation for a right peri-silvian polymicrogyria. He was excluded from surgery due to extent of the epileptogenic zone and the risk of visual field deficits. RF-TC was attempted to ablate the most epileptogenic zone identified by SEEG. After RF-TC, the patient reported an increase in seizure severity/frequency and experienced episodes of postictal psychosis. Off-label cannabidiol treatment led to improved seizure control and resolution of postictal psychosis.Patients with polymicrogyria (PwP) may present with a disruption of normal anatomy and the co-existence between epileptogenic zone and eloquent cortex within the malformation.RF-TC should be considered in PwP when they are excluded from surgery for prognostic and palliative purposes. However, given the complex interplay between pathological and electrophysiological networks in these patients, the remote possibility of clinical exacerbation after RF-TC should also be taken into account.

Abstract Background Lafora disease (LD) is a rare fatal autosomal recessive form of progressive myoclonus epilepsy. It affects previously healthy children or adolescents, causing pharmacoresistant epilepsy, myoclonus and severe psychomotor deterioration. This work aims to describe the clinical course of LD and identify predictors of outcome by means of a prognostic systematic review with individual participant data meta-analysis. Methods A search was conducted on MEDLINE and Embase with no restrictions on publication date. Only studies reporting genetically confirmed LD cases were included. Kaplan–Meier estimate was used to assess probability of death and loss of autonomy. Univariable and multivariable Cox regression models with mixed effects (clustered survival data) were performed to evaluate prognostic factors. Results Seventy-three papers describing 298 genetically confirmed LD cases were selected. Mean age at disease onset was 13.4 years (SD 3.7), with 9.1% aged ≥ 18 years. Overall survival rates in 272 cases were 93% [95% CI 89–96] at 5 years, 62% [95% CI 54–69] at 10 years and 57% [95% CI 49–65] at 15 years. Median survival time was 11 years. The probability of loss of autonomy in 110 cases was 45% [95% CI 36–55] at 5 years, 75% [95% CI 66–84] at 10 years, and 83% [95% CI 74–90] at 15 years. Median loss of autonomy time was 6 years. Asian origin and age at onset

Abstract Objective Many neurological manifestations are associated with COVID‐19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID‐19 patients. Cytokine storm is also associated with immune effector cell‐associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T‐cell (CAR‐T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID‐19‐related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings. Methods Narrative literature review. Results Comparisons between COVID‐19‐related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection‐associated encephalopathies. Interpretation COVID‐19‐related encephalopathy and ICANS are characterized by a predominant electro‐clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm‐associated encephalopathy (CySE), and its diagnostic criteria.

Abstract Objective Clinical care of rare and complex epilepsies is challenging, because evidence‐based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies. Methods Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web‐based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht‐like diseases. A consensus‐based questionnaire was generated for each disease. Results Twenty‐six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht‐like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers. Significance The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.

Abstract The study aims to characterize the epilepsy phenotype of maternally inherited Leigh's syndrome (MILS) and neuropathy, ataxia, retinitis pigmentosa (NARP) due to mutations in the mitochondrial ATP6 gene and to correlate electroclinical features with mutant heteroplasmy load (HL). We investigated 17 individuals with different phenotype, from asymptomatic carriers to MILS: 11 carried the m.8993T> G mutation, 5 the m.8993T> C and one the novel, de novo m.8858G> A mutation. Seizures occurred in 37.5% of patients, EEG abnormalities in 73%. We ranked clinical and EEG abnormalities severity and performed quantitative EEG to estimate Abnormality Ratio (AR) and Spectral Relative Power (SRP). Spearman’s rho and Kruskal–Wallis test were used for correlation with heteroplasmy load (HL). HL correlated with disease severity (Rho = 0.63, P = 0.012) and was significantly higher in patients with seizures or EEG abnormalities (P = 0.014). HL correlated with EEG severity score only for the m.8993T> G (Rho = 0.73, P = 0.040), showing a trend toward a positive correlation with AR and delta SPR, irrespective of the mutation.

The aim of this report is to describe clinical, EEG, and neuroimaging findings in a patient with Unverricht-Lundborg disease (ULD), the most common form of progressive myoclonus epilepsy (PME). A 23-year-old male with genetically confirmed ULD had a phenotype consisting of myoclonus, generalized seizures, intellectual disability, ataxia, and dysarthria. Myoclonus and gait disturbance were strongly ameliorated by alcohol consumption. EEG revealed a posterior dominant rhythm with alpha variant, mild bilateral slowing, and anterior-predominant epileptiform abnormalities. Brain MRI showed mild cerebellar atrophy. FDG-PET revealed hypometabolism more prominent in the posterior brainstem, thalami, frontal and parietal lobes.This report confirms that alcohol may ameliorate myoclonus in a subset of patients with PME, including genetically confirmed ULD. In addition, the presence of FDG-PET hypometabolism predominant in the frontoparietal region and thalami has not been previously described in ULD, yet is consistent with previous brain morphometry studies showing motor cortex and thalamic atrophy in ULD, and brings into question the possibility of a shared metabolic pattern with other PMEs, notably Lafora disease.

MECP2 duplication syndrome (MDS) is a rare and severe neurodevelopmental disorder frequently associated with epilepsy. Different seizure types and electroencephalographic (EEG) patterns were described in patients with MDS, although it lacks a specific phenotype.We report on an adult patient with long-term epilepsy showing an evolution of the EEG pattern that progressively changed into burst suppression (BS) during sleep. As BS has not been previously reported in MDS, this report expands the neurophysiological phenotype of MDS and further suggest the possible occurrence of a longitudinal spectrum of seizure types and EEG patterns in MDS.

Epilepsy with auditory features (EAF) is a focal epilepsy belonging to the focal epileptic syndromes with onset at variable age according to the new ILAE Classification. It is characterized by seizures with auditory aura or receptive aphasia suggesting a lateral temporal lobe involvement of the epileptic discharge. Etiological factors underlying EAF are largely unknown. In the familial cases with an autosomal dominant pattern of inheritance several genes have been involved, among which the first discovered, LGI1, was thought to be predominant. However, increasing evidence now points to a multifactorial etiology, as familial and sporadic EAF share a virtually identical electro-clinical characterization and only a few have a documented genetic etiology. Patients with EAF usually have an unremarkable neurological examination and a good response to antiseizure medications. However, it must be underscored that total remission might be lower than expected and that treatment withdrawal might lead to relapses. Thus, a proper understanding of this condition is in order for better patient treatment and counseling. Further studies are still required to further characterize the many facets of EAF.

Familial cortical myoclonic tremor (FAME) has so far been mapped to regions on chromosome 2, 3, 5 and 8 and pentameric repeat expansions in SAMD12 were identified as cause of FAME1. Here, Corbett et al. identify ATTTT/ATTTC repeat expansions in intron 1 of STARD7 in individuals with FAME2.”

Abstract Sleep-related hypermotor epilepsy (SHE), formerly known as Nocturnal Frontal Lobe Epilepsy is a focal epilepsy characterized by seizures with complex hyperkinetic automatisms and/or asymmetric tonic/dystonic posturing occurring mostly during sleep. SHE is a rare disease with an estimated minimum prevalence of 1.8/100,000 individuals and represent about 10% of drug-resistant surgical cases. This disorder, though uncommon, is of considerable interest to a broad spectrum of specialists, from child neurologists to neurosurgeons. Distinguishing this condition from non-epileptic paroxysmal behaviour occurring physiologically or pathologically during sleep is often difficult and sometimes impossible on clinical grounds alone, even for experienced epileptologists and sleep physicians. Recognized aetiologies of SHE are heterogeneous and include acquired injuries, genetic causes and structural anomalies such as focal cortical dysplasia. Multiple aetiologies (structural-genetic) are also possible. Non-specific clinical features distinguished different aetiologies even if SHE due to structural lesions usually manifests with early-onset drug-resistant seizures and showed a worse long-term prognosis. The causative genes for SHE are multiple and encode for proteins involved in different molecular pathways. The cholinergic system and the mTOR pathway are the most relevant. This review will provide an exhaustive overview of the genetic background of SHE.

Abstract Background Lafora disease (LD) is a rare, lethal, progressive myoclonus epilepsy for which no targeted therapy is currently available. Studies on a mouse model of LD showed a good response to metformin, a drug with a well known neuroprotective effect. For this reason, in 2016, the European Medicines Agency granted orphan designation to metformin for the treatment of LD. However, no clinical data is available thus far. Methods We retrospectively collected data on LD patients treated with metformin referred to three Italian epilepsy centres. Results Twelve patients with genetically confirmed LD (6 EPM2A, 6 NHLRC1) at middle/late stages of disease were treated with add-on metformin for a mean period of 18 months (range: 6–36). Metformin was titrated to a mean maintenance dose of 1167 mg/day (range: 500–2000 mg). In four patients dosing was limited by gastrointestinal side-effects. No serious adverse events occurred. Three patients had a clinical response, which was temporary in two, characterized by a reduction of seizure frequency and global clinical improvement. Conclusions Metformin was overall safe in our small cohort of LD patients. Even though the clinical outcome was poor, this may be related to the advanced stage of disease in our cases and we cannot exclude a role of metformin in slowing down LD progression. Therefore, on the grounds of the preclinical data, we believe that treatment with metformin may be attempted as early as possible in the course of LD.

Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox–Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period.Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline.Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite.Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.

Objectives: We explored the impact of the coronavirus disease-19 (COVID-19) emergency on the health of people with epilepsy (PwE). We also investigated their attitude toward telemedicine.Methods: The PubMed database up to September 10, 2020 was searched for questionnaire-based studies conducted in PwE during the COVID-19 emergency, and the literature retrieved was reviewed. In addition, all patients who had a telephone consultation with our center between May 7 and July 31, 2020 were invited to fill in a 57-item online questionnaire focusing on epilepsy and comorbidities, any changes in lifestyle or clinical conditions and any emergency-related problems arising during the COVID-19 emergency, and their views on telemedicine. Associations between variables were detected through X2 test and Fisher's exact test. Univariate and multivariate logistic regression models were used to evaluate the effects of different factors on clinical conditions.Results: Twelve studies met the literature search criteria. They showed that the rate of seizure worsening during the emergency ranged from 4 to 35% and was mainly correlated with epilepsy severity, sleep disturbances and COVID-19-related issues. Our questionnaire was filled in by 222 PwE or caregivers. One hundred (76.6%) reported unchanged clinical conditions, 25 (11.3%) an improvement, and 27 (12%) a deterioration. Reported clinical worsening was associated with a psychiatric condition and/or medication (OR = 12.59, p < 0.001), sleep disorders (OR = 8.41, p = 0.001), limited access to healthcare (OR = 4.71, p = 0.016), and experiencing seizures during the emergency (OR = 4.51, p = 0.007). Telemedicine was considered acceptable by 116 subjects (52.3%).Conclusions: Most PwE did not experience a significant change in their clinical conditions during the COVID-19 emergency. However, severity of epilepsy, concomitant disability, comorbid psychiatric conditions, sleep disorders and limited access to healthcare may affect their health.

Introduction: Neurological manifestations are emerging as relatively frequent complications of corona virus disease 2019 (COVID-19), including stroke and encephalopathy. Clinical characteristics of the latter are heterogeneous and not yet fully elucidated, while the pathogenesis appears related to neuroinflammation in a subset of patients.Case: A middle-aged man presented with acute language disturbance at the emergency department. Examination revealed expressive aphasia, mild ideomotor slowing, and severe hypocapnic hypoxemia. Multimodal CT assessment and electroencephalogram (EEG) did not reveal any abnormalities. COVID-19 was diagnosed based on chest CT findings and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcription PCR (RT-PCR) on nasopharyngeal swab. The following day, neurological symptoms progressed to agitated delirium and respiratory status worsened, requiring admission to the ICU and mechanical ventilation. Brain MRI and cerebrospinal fluid (CSF) studies were unremarkable. RT-PCR for SARS-CoV-2 on CSF was negative. He received supportive treatment and intravenous low-dose steroids. His neurological and respiratory status resolved completely within 2 weeks.Conclusions: We report a patient with reversible COVID-19-related encephalopathy presenting as acute aphasia, mimicking stroke or status epilepticus, eventually evolving into delirium. Although large-vessel stroke is frequently encountered in COVID-19, our case suggests that focal neurological deficits may occur as the earliest feature of encephalopathy. Neurological status reversibility and the absence of abnormalities on brain MRI are consistent with a functional rather than a structural neuronal network impairment.

Objectives: To evaluate functional connectivity (FC) in patients with sleep-related hypermotor epilepsy (SHE) compared to healthy controls. Methods: Resting state fMRI was performed in 13 patients with a clinical diagnosis of SHE (age=38.3±11.8years, 6M) and 13 matched healthy controls (age=38.5±10.8years, 6M).Data were first analysed using probabilistic independent component analysis (ICA), then a graph theoretical approach was applied to assess topological and organizational properties at the whole brain level. We evaluated node degree (ND), betweenness centrality (BC), clustering coefficient (CC), local efficiency (LE) and global efficiency (GE). The differences between the two groups were evaluated non-parametrically. Results: At the group level, we distinguished 16 RSNs (Resting State Networks). Patients showed a significantly higher FC in sensorimotor and thalamic regions (p

Introduction: Disorders of Arousal (DoA) are NREM parasomnias that have been typically regarded as self-limited childhood manifestations. It is now clear that DoA can persist in adults, often presenting with distinctive characteristics. So far, few studies have described the clinical course and characteristics of DoA in adulthood, therefore a large part of their semiology is ignored. The aim of this study is to describe the clinical manifestations of DoA in an adult population and to provide a pathophysiological interpretation of their features.Methods: We screened our database for all 1,600 adult (≥15 years) patients with sleep-related motor behaviors between 1995 and 2016. We identified 45 patients with typical DoA episodes, of whom a complete history, neurological examination and diagnostic video-polysomnography (VPSG) were available. All patients provided a detailed description of their episodes (with particular regards to semiology, frequency, and association with stressful life events) in different life periods. VPSG recordings were reviewed and DoA episodes were identified and assigned to three different categories according to their complexity.Results: Our population was composed of 45 adult patients ranging between 15 and 76 years. Sleepwalking was reported by 86% of patients, possibly associated with complex interactions with the environment and violent behaviors in 53% of cases; distressing mental contents were reported by 64%. Recall of the episodes was reported in 77% of patients. Non-restorative sleep was reported in 46% of patients. Stress was a potential episode trigger in 80% of patients. VPSG recordings documented 334 DoA episodes. According to our classification of motor patterns, 282 episodes (84%) were Simple Arousal Movements (SAMs), 34 (10%) Rapid Arousal Movements (RAMs) and 18 (5%) Complex Arousal Movements (CAMs).Discussion: Our study confirms that DoA in adulthood present with distinctive characteristics, such as non-restorative sleep, violence and complex, or bizarre behaviors. Alternative classifications of DoA based on motor patterns could be useful to characterize DoA episodes in adults, as different motor patterns often coexist in the same individual and minor episodes are more common but generally underreported by patients. Prospective studies are needed for a definitive characterization of DoA in adulthood throughout the life course.